1-(3&#39;, 4&#39;-di-lower-alkylphenyl)-2-[phenylpyridyl-(2&#39;)-propylamino]-propanol-(1) and derivatives thereof



United States Patent 1 (3',4' DI LOWER-ALKYLPHENYL)-2-[PHENYL- PYRIDYL(2') PROPYLAMINO1-PROPANOL-(1) AND DERIVATIVES THEREOF Gustav Ehrhart,Bad Soden, Taunus, Ernst Lindner and Giinter Hfirtfelder, Frankfurt amMain, and Heinrich Ott, Eppstein, Taunus, Germany, assignors to Fair]:-werke Hoechst Aktiengesellschaft vormals Meister Lucius & Bruning,Frankfurt am Main, Germany, a corporation of Germany No Drawing. FiledOct. 27, 1966, Ser. No. 589,816

Claims priority, application Germany, Nov. 5, 1965, F 47 601 2 Claims.Ci. 260-296) The present invention relates to basically substitutedphenyl-propane derivatives corresponding to the general Formula I R: OHR4 (a) reducing compounds of the general Formula II @ymamglaatg in whichR represents hydrogen or the benzyl group and R -R have the meaningsgiven above,

(b) treating compounds of the general Formula III in which R-R have themeanings given above and R represents an alkyl or the benzyl group, withether separating agents or by catalytic hydrogenation,

(c) hydrolizing in an alkaline or acid medium compounds of the generalFormula IV R R OAc R onoHzo H2l 1'( 1 Jar-(EEG Cy in which RR have themeanings given above and Ac represents an acyl group,

((1) catalytically hydrogenating compounds of the general Formula V RR:X R4 3,414,578 Patented Dec. 3, 1968 "ice in which R-R have the meaningsgiven above and X represents an oxygen atom or the group (e) reactingcompounds corresponding to the general Formula VI Cy I) in which R hasthe meaning given above, either with ethyleneoxides corresponding to thegeneral Formula in which R R have the meanings given above or condensingcompounds corresponding to the Formula VI with compounds correspondingto the general Formula VIII X B3 (VIII) in which R R have the meaningsgiven above and reducing the condensation product simultaneously orsubsequently,

(f) condensing phenyl-propionaldehydes corresponding to the generalFormula IX C H- C H2-CHO with compounds corresponding to the generalFormula R: R4 HN--CQ I l i k Ra (X) in which X, R and R R have themeanings given above and reducing the condensation productsimultaneously or subsequently,

(g) reducing compounds of the general Formula XI in which X and R-R havethe meanings given above with complex metal hydrides,

during all the above-mentioned methods the subsequent cleavage of anN-benzyl group which may be present, and converting the basic compoundsobtained into their physiologically tolerated salts, if desired, bytreatment with inorganic or organic acids.

For preparing the amino alcohols of the general Formula I according tothe method described sub (a) the amino ketones of the general Formula IIare reduced.

The reduction of the keto group can be carried out for instance bycatalytic hydogenation with the aid of metals of the 8th group of thePeriodic System, preferably by means of nickel catalysts, in thepresence of appropriate solvents such, for instance, as aqueousalcohols, alcohols or water. The compounds may likewise be reduced bymeans of nascent hydrogen, for instance, aluminium amalgam and alcohol,sodium amalgam, lithium-aluminium hydride, sodium boron hydride orlikewise electrolytically.

The starting ketones of the general Formula II can be prepared, forinstance, by reaction of l-phenyl-lpyridyl-(2)-propyl(3)-amine withhalogenated ketones of the general formula This reaction isadvantageously carried out in the presence of agents splitting offhydrogen halides. The starting substances corresponding to the generalFormula II may likewise be prepared by reactingl-phenyl-lpyridyl-(2)-3-halogen-propanes with the correspondingamino-ketones of the general formula 2 Nmawg The products correspondingto the general Formula I can likewise be prepared by dealkylating in theusual manner according to the method described sub (b) correspondingcompounds which as R contain an alkyl group, or by splitting off abenzyl group from compounds containing the latter as R The dealkylationcan be carried out, for instance, by heating the compounds with hydrogenbromide or with aluminium chloride or with pyridinehydro-chloride. Thebenzyl radical is advantageously separated catalytically while usingnoble metal catalysts, such for instance as palladium black, or byboiling with hydrobromic acid.

The starting substances corresponding to the general Formula III usedaccording to the operation method described sub (b) are prepared in ananalogous manner to that applied for the compounds of the generalFormula II. 1-phenyl-1-pyridyl(2)-propyl(3)-amine can be reacted, forinstance, with halogenated ethers corresponding to the formula R2Hal(3H-CH or with oxo-compounds of the general formula benzyl R aneventually present CN-group being split off by a method known per se.The N-benzyl group can be separated prior to or after the cleavage ofether, preferably by catalytic hydrogenation. If R likewise represents abenzyl group, the two 0- and N-benzyl groups can be separated off in oneoperation by catalytic hydrogenation.

The starting materials of the general Formula IV used for the operationmethod mentioned sub (0) can be prepared correspondingly as describedfor compounds II and III. As starting substances there are mentioned,for instance, compounds of the general Formula IV, in which Acrepresents the acetyl, propionyl or benzoyl radical. The hydrolysis iscarried out in the usual manner in an aqueous-alkaline medium or withalcoholic or aqueousalcoholic solution. It can likewise be realized bymeans of dilute acids such as hydrochloric acid or sulfuric acid.

Another method of operation of the process according to (d) consists inhydrogenating the CC-double linkage in compounds of the Formula V. Thereduction is advantageously carried out by catalytic hydrogenation byusing metals of the 8th group of the Periodic System, preferably withprecious metals. As solvents there are used the solvents usually appliedfor the hydrogenation, for instance, alcohols, water or aqueousalcohols.

The starting compounds of the general Formula V are prepared, forinstance, by condensation of compounds of the general Formula XII withamines of the general Formula XIII (XII) (XIII) and partialhydrogenation according to Bull. Soc. Chim. France, 1952, p. 1046.

A further advantageous possibility for preparing the desired compoundscomprises (e) reacting amines of the general Formula VI withethylene-oxides of the general Formula VII, the reaction advantageouslybeing performed in the presence of a solvent such as, for example,ethanol, and at an elevated temperature.

As ethylene-oxides there are mentioned, for instance:

1- 3,4-dimethylphenyl) -ethylene-oxide,

1- (3 ,4-dimethylphenyl) -2-methyl-ethylene-oxide, 1- 3,4-diethyl-phenyl-ethylene-oxide,

1- (3 ,4-diethylphenyl -2-methyl-ethylene oxide.

A further possibility of preparing the compounds claimed, by startingfrom amines of the general Formula VI consists in subjecting toreduction ketones or aldehydes of the general Formula VIII in thepresence of said amines. As ketones or aldehydes of said type thefollowing compounds may be used:

1-(3,4-dimethylphenyl) -1,2-dioXo-propane,1-(3,4-diethylphenyl)-1,2-dioxo-propane, (3,4-dimethylphenyl)-1,2-dioxo-ethane, (3,4-diethylphenyl)-1,2-dioXo-ethane,(3,4-dimethylphenyl) -glycol-( 2) -aldehyde,(3,4-dimethylphenyl)-1-hydroxy-2-oxo-propane, (3 ,4-diethylphenyl-glycol( 2) -aldehyde,

(3 ,4-diethyl-phenyl l -hydroXy-2-oXo-prop ane.

The reduction favorably proceeds by catalytic hydrogenation of equimolaramounts of the two compounds in the presence of an inert solvent. Ascatalysts, metals of the 8th group of the Periodic System are used,preferably precious metals.

The most suitable solvents are those generally used for hydrogenation,for instance, alcohols, aqueous alcohols or water. Nickel catalysts maylikewise be used. It is likewise possible first to condense the oxocompounds of the Formula VIII with the amines of the Formula VI and thento reduce the condensation product with nascent hydrogen, for instancewith aluminium amalgam and alcohol, sodium amalgam,lithium-aluminium-hydride or so dium boron-hydride. The reduction maylikewise be carried out electrolytically. The condensation ischaracterized by the fact that preferably the keto-group adjacent to themethyl group or the aldehyde group reacts with the amine; the other OX0group may be reduced simultaneously or subsequently to the hydroxylgroup in the manner mentioned sub (a).

An appropriate amine which may be used as starting substance for thereaction according to (e), is for example3-phenyl-3-pyridyl(2)-propyl-amine.

According to the same method there can likewise be useda-hydroxy-ketones or aldehydes of the Formula VIII in which thehydroxy-group is protected by an alkyl, benzyl or acyl group which maysubsequently be separated according to (b) or (c).

A further possibility of preparing the products according to theinvention consists in condensing phenylpyridyl(2)-propionaldehyde of theFormula 1X with amino-alcohols r amino-ketones of the Formula Xaccording to the method described sub (f). The reaction of the aldehydeswith the amino alcohols with simultaneous or subsequent reduction is, inprinciple, carried out according to the method described sub (e) for theprepara tion of the products of the invention, by starting from 1-phenyl-3-amino-propanes of the Formula VI and 0x0- compounds of thegeneral Formula VHI.

As starting substances for said reaction the following amines may beused:

1 3 ,4-dimethylphenyl) l-hydroxy-2-amino-ethane, 1- 3 ,4-dimethylphenyl-1-hydroxy-2-amino-propane, 1- 3,4-diethylphenyl)-1-hydroxy-2-amino-ethane,

1- 3 ,4-diethylphenyl)-1-hydroxy-2-amino-propane as well as thel-oxo-2-amino-ethanes corresponding to the above-mentionedl-hydroxy-compounds.

According to the same method, amino alcohols of the Formula X maylikewise be used in which the hydroxy group is protected by an alkyl,benzyl or acyl radical 'which may subsequently be separated according to(b) or (c).

According to a further method of operation according to (g) it islikewise possible to reduce carboxylic acid amides of the Formula XI,most favorably by means of lithium-aluminium-hydride. The reduction isadvantageously carried out in the presence of inert organic solventssuch as ether, dioxane or tetrahydrofurane. It is suitable to added theamide to the lithium-aluminiumhydride suspension in one of theabove-mentioned solvents, to boil the reaction mixture for some timeunder reflux, to decompose it cautiously by means of water and to workit up in the usual manner by separating the organic from the inorganicconstituents. The reduction of the carboxylic acid amides in order toobtain the amines is likewise possible by electrolysis. The amides ofthe Formula XI can be prepared in the usual manner from thecorresponding pyridyl-propionic acid chlorides by reaction with aminesof the Formula X.

The products of the invention, constituting basic compounds, can beconverted into the corresponding salts by means ofinorganic or organicacids. As inorganic acids there may be used: hydrohalic acid such ashydrochloric acid and hydrobrornic acid, sulfur acid, phosphoric acidand amidosulfonic acid. As organic acids the following are mentioned,for example: acetic acid, propionic acid, lactic acid, glycolic acid,gluconic acid, maleic acid, succinic acid, tartaric acid, benzoic acid,salicylic acid, citric acid, aceturic acid, hydroxy-ethane-sulfonic acidand ethylene-diamine-tetracetic acid.

The products of the invention are valuable medicaments having a veryfavorable action on cardiac and blood vascular circulation. For example,a single injection of 5 ofl-(3,4'-dimethylphenyl)-2-(m-methoxy-diphenylpropylamino)-propanol-( 1)in the test on the isolated heart of guinea pigs according toLangendorff causes an increase of the perfusion of the coronary vesselswithin the same range as that caused by administering 57 of the knowncompounds 1-phenyl-2-[3',3'-diphenyl-propyl- (1')-amino] -propane.

The advantage of the new products consists, however, above all, in thatin addition to their dilating action on the coronary vessels they showan excellent B-sympathicolytic action. fi-sympathicolytically activesubstances inhibit the effect of adrenalin and isopropyl-noradrenalinwhich consists in increasing the heart rate and the contracting power ofthe heart. Adrenalin and isopropylnoradrenalin likewise activate cardiacmetabolism indirectly and by the above-mentioned actions also directly.An activation of the sympathetic nervous system starting at anunsuitable moment for which the two substances constitute a particularexample, may cause anoxemia of the heart, particularly if the coronaryvessels show constrictions (due to calcareous degeneration). Afl-sympathicolytic action protects the heart against a high increase inmetabolism.

In addition to their favorable action on cardiac and blood vascularcirculation, the products of the present invention show a favorablehypotensive effect.

For example, the1-(3',4'-dimethylphenyl)-2-[phenylpyridyl-(2")-propylamino]-propanol l)hydrochloride lowers the blood pressure considerably and for a prolongedperiod in rats suffering from renal high pressure.

In 11 rats suffering from renal high pressure, the blood pressureamounted, on an average, to 192 mm. Hg. Two hours after subcutaneousadministration of 40 milligrams/ kilogram of the product of theinvention the blood pressure diminished to 136 mm. Hg and 24 hours afterinjection it amounted to 168 mm. Hg, i.e. it had not yet attained againthe initial value.

The same product moreover shows a strong [i-sympathicolytic action. Inthe tracheal chain according to Castillo it provokes with only 2.5 per50 cc. of Tyrodes solution a reduction by about 50% of the action of 5of isopropylnoradrenalin.

In the heart of guinea pigs isolated according to the method ofLangendorlf the same product by permament infusion of 0.1 per minutecaused a reduction by about one third of the increase of the heart rateprovoked by 0.1 of isopropyl-noradrenalin. 15 of the product of thepresent invention distinctly activated the coronary perfusion of theheart of guinea pigs isolated according to Langendorlf.

The combination of the 3 effects mentioned above imparts to the productsof the present invention special advantages in comparison with thecompounds hitherto known. The products of the present invention areespecially suitable for the treatment of hypertonia, since inhypertonics the dilatory action on the coronary vessels is of advantage,the heart of said patients showing a considerably increased mass ofmuscles 'which must be nourished. Furthermore, the hypertonic tends toarteriosclerosis of the cardiac coronary vessels the consequences ofwhich may be compensated by a dilatation of the small vessels free fromcalcification.

The following example serves to illustrate the invention but it is notintended to limit it thereto:

EXAMPLE 1- 3',4'-dimethylphenyl -2- [phenyl-pyridyl- (2" propylamino]-propanol-( 1 -hydrochloride 7.1 grams offl-phenyl-B-pyridyl-(Z)-propionaldehyde and 6.0 grams ofl-(3',4-dimethylphenyl)-2-arninopropanol-(l) (melting point C.)(prepared by bromination of 3,4-dimethyl-propiophenone, reaction of thebromine compound with benzylamine and subsequent catalytichydrogenation) are dissolved together in 30 cc. of benzene, whereby thesolution is slightly heated. The benzene is distilled off under reducedpressure, the residue is dissolved in methanol and 1 gram ofsodium-boronhydride is added in small portions, causing a vividreaction. The product is allowed to stand for about 15 minutes,acidified by means of dilute hydrochloric acid and the methanol isdistilled off under reduced pressure. The residue is shaken with dilutesodium hydroxide solution and ether. The ether phase is separated, driedby means of potassium carbonate and the ether is distilled off. Theresidue is dissolved in a small amount of methanol and hydrochloric acidis added. After elimination of the solvent by distillation the residueis recrystallized from a mixture of acetone and ether. 9.5 grams of1-(3,4-dimethyl-phenyl)-2-[phenyl-pyridyl (2") propylamino]-propanol-(l)-hydrochloride of a melting point of 196- 197 C. areobtained.

We claim:

1. A phenylpropane of the general formula 8 wherein R representshydrogen or the methyl group, R and R represent alkyl groups containingat most 4 carbon atoms, and a pharmaceutically acceptable acid additionsalt thereof.

2. 1-(3,4'-dimethylphenyl) 2 [phenyl-pyridyl-(2)- propylamino]-propanol- 1) References Cited Barron et al.: J. Med. Chem, vol. 8 (6),pp. 836-41, 1965.

Barron et a1.: Journal Pharm. and PharmacoL, vol. 17 (8), pp. 509-16,1965.

Chem. Abstracts, vol. 63, par. 12,140, October 1965.

Chem. Abstracts, vol. 63, par. 18,021, December 1965.

HENRY R. JILES, Primary Examiner.

A. L. ROTMAN, Assistant Examiner.

P0405) UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3, l14,578 Dated December 3, 1968 Inventor) HANNS HANINA LEHR and MILANMITROVIC It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

7 Column 6, line 56, claim 3 "claim 2" should be:

claim 1 SIGNED AND SEALED MAY 1 9 I970 Attcst:

WILLIAM 3- 50mm, JR. Edwlrdnmmhmj" Domini-om o: hunts Attosting Officer

1. A PHENYLPROPANE OF THE GENERAL FORMULA